Abstract
The Id proteins play an important role in proliferation, differentiation, and tumor development. We report here that Id gene expression can be regulated by the insulin-like growth factor I receptor (IGF-IR), a receptor that also participates in the regulation of cellular proliferation and differentiation. Specifically, we found that the IGF-IR activated by its ligand was a strong inducer of Id2 gene expression in 32D murine hemopoietic cells. This activation was not simply the result of cellular proliferation, as Id2 gene expression was higher in 32D cells stimulated by IGF-I than in cells exponentially growing in interleukin-3. The up-regulation of Id2 gene expression was largely dependent on the presence of insulin receptor substrate-1, a major substrate of the IGF-IR and a potent activator of the phosphatidylinositol 3-kinase (PI3K) pathway. The role of PI3K activity in the up-regulation of Id2 gene expression by the IGF-IR was confirmed by different methods and in different cell types. In 32D cells, the up-regulation of Id2 gene expression by the PI3K pathway correlated with interleukin-3 independence and inhibition of differentiation.
Highlights
The Id proteins are helix-loop-helix proteins that form heterodimers with a large family of other helix-loop-helix proteins, mostly transcriptional activators, that have a basic region in addition to the helix-loop-helix region [1]
Id2 RNA was barely detectable in 32D insulin-like growth factor I receptor (IGF-IR)/insulin receptor substrate-1 (IRS-1) cells growing in IL-3, and its levels increased sharply when the cells were shifted from IL-3 (Time 0 lane) to IGF-I, with a peak at 6 h
1) Id2 gene expression is up-regulated by an activated IGF-IR both in hemopoietic cells and in other cell types
Summary
Using inhibitors of PI3K and a mutant IRS-1 that fails to activate PI3K, we show that, in 32D IGF-IR cells, PI3K activation plays an important role in the up-regulation of Id2 gene expression. We have confirmed these findings in two different cell types, 293T and LNCaP cells. Other pathways probably lead to Id2 gene expression, this is, to our knowledge, the first signal transduction pathway to be identified These findings offer an explanation for the dual signaling of the IGF-IR in these cells
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